PROJECT SUMMARY Synthetic polymer biomaterials have been widely used in biomedical areas. However, FDA-approved aliphatic polyesters, such as polylactide (PLA) and polycaprolactone (PCL), need additional modification for in vivo applications requiring hydrophilicity and functionalities. PEGylated therapeutics have broad clinical applications; however, PEG immunogenicity and reduced bioactivity of therapeutics resulted from PEGylation significantly restrict their biomedical efficacy. Recently zwitterionic polymers (ZPs) have emerged as promising hydrophilic biomaterials that can promote circulation time and maintain the bioactivity of conjugated therapeutics, without inducing immunological response. However, the inability of conventional ZPs to degrade can result in polymer accumulation and cause severe long term side effects for in vivo clinical applications. In this R21 proposal, we aim to integrate the FDA-approved aliphatic polyesters with zwitterions for the development of a class of novel polymer biomaterials. Based on the significant preliminary results, the following two specific aims are proposed: 1) to develop biodegradable ZPs and ZP-based crosslinked materials (i.e. nanocapsules and films), and 2) to understand their biomedical-related properties. The hypothesis of this proposal is that ZPs with aliphatic polyester backbones and zwitterionic side groups can be prepared by thiol-ene click functionalization of ene-functionalized aliphatic polyesters with zwitterionic thiols, and they not only are biodegradable and biocompatible, but also maintain the favorable biomedical-related properties of conventional ZPs. We will design and synthesize a library of well-defined ZPs with PLA or PCL-based backbones that carry different mol% of carboxybetaine, sulfobetaine, or phosphobetaine-based zwitterions. Moreover, these ZPs can possess ene-functionalities for further modification, and the synthetic principle for the conversion of these ZPs to ZP-based nanocapsules and films through thiol-ene crosslinking will be demonstrated. Comprehensive analytical approaches will be employed to characterize the ZPs and their derived materials for verifying their well-controlled structures. To achieve insightful understanding on their structure-property relationship, systematic property studies will be performed. Their hydrophilicity, degradability, and anti-biofouling property will be investigated. In vitro assessment of cytotoxicity and in vivo study of systemic toxicity will be conducted to evaluate their biocompatibility. Circulation time and biodistribution of the ZP-based nanocapsules will also be measured using mouse model to verify that they can have long circulation, without causing long-term polymer accumulation. Together, the proposed R21 studies promise to not only establish the synthetic methodology for aliphatic polyester-based biodegradable ZPs and ZP-based materials, but also provide key insights into their structure-dependent biomedical-relevant properties. These studies will lay a solid foundation for the further development of biodegradable ZP-modified therapeutics and other products for in vivo clinical applications.